猎奇重口

The overarching goal of the Cellular and Molecular Oncology (CMO) Research Program is to conduct basic, cancer-relevant research that is focused on discovering the cellular and molecular mechanisms that govern tumor initiation and cancer progression. Our goals are to translate our discoveries into diagnostic and prognostic biomarkers and targets for intervention in clinical and community settings, with a particular emphasis on those cancers with high incidence, mortality, or disparity in our catchment area.

The CMO Program has three overall themes that embody its Scientific Aims:

• Carcinogenic Mechanisms of Environmental Exposures: To discover the molecular and cellular mechanisms by which environmental carcinogens and behavioral risk factors relevant to our catchment area promote cancer.
• Genome Regulation: To define the mechanisms and pathways by which genome stability, epigenetic alterations, and transcriptional regulation are disrupted in cancer cells.
• Cellular Signaling and the Tumor Microenvironment: To determine how cell signaling pathways, cellular activities, and cell-cell interactions are altered during cancer initiation and progression and within the tumor microenvironment.

Aim 1: Carcinogenic Mechanisms of Environmental Exposures: To discover the molecular and cellular mechanisms by which environmental carcinogens and behavioral risk factors relevant to our catchment area promote cancer.  The effects of environmental exposures on carcinogenesis are the focus of multiple groups in CMO. The University of New Mexico Center for Metals in Biology and Medicine (NIGMS P20GM130422) directed by Campen (CCPS) is continuing to support the research of three junior CMO members to investigate the roles of tungsten in breast cancer (Bolt; Bolt, Adv. Pharmacol. 2023); iron in metabolic reprogramming in colon cancer (Xue; Liu et al., Inflamm. Bowel Dis. 2023; Kim et al., Adv. Sci. 2023;); and particulate arsenic-stimulated oxidative damage and disruption of DNA repair in lung (Zhou; Speer et al., Comm Biol 2023; Medina et al., Water 2023;). CMO members Blossom and Hudson also serve as deputy director and mentoring director, respectively, on this CoBRE grant.

The groups of Hudson and Zhou made important progress in understanding the molecular mechanisms by which arsenic and uranium, metals that are significant environmental contaminants in NM, cause DNA damage and inhibit DNA repair pathways that contribute to genome instability. Their ongoing research on the co-carcinogenic role of arsenic and UV radiation (UVR), is supported by a MPI grant to Hudson and Dr. Liu (Stonybrook) to investigate the mutational signatures of this combined environmental exposure (NIEHS R01ES030993). Co-exposure led to greater than 2-fold enrichment of UVR mutational burden and identified a novel feature only associated with arsenic plus UV co-exposure in human keratinocytes and mouse skin (collaboration with Zhou: Speer et al., Adv. Pharmacol. 2023; Speer et al. Comm. Biol. 2023).  Hudson used a preclinical mouse model to show that zinc supplementation reduced the amount of arsenic detected in tissues (Dashner-Titus et al., Toxicol. Appl. Pharmacol. 2023). This research is also being translated to the NM population through an interventional clinical trial (NCT03908736) to test the potential of supplemental zinc to overcome DNA damage, oxidative stress and inflammation caused by environmental metal exposure in tribal communities. Broad inter-programmatic collaboration is evident in the renewed “猎奇重口Metal Exposure Toxicity Assessment on Tribal Lands in the Southwest (METALS) Superfund Basic Science Research and Training Program” (P42ES025589 PI: Lewis). The NIEHS P30 Center ES032755, “New Mexico Integrative Science Program Incorporating Research in Environmental Sciences (NM-INSPIRES)” is led by CMO members Blossom (Director) and Hudson (Deputy Director) with Campen (CCPS; Director of Professional Development). This Center supports studies on the biological effects of environmental contaminants, including cancer outcomes, in the NM catchment area. CMO member Luo is the director of the Biostatistics and Data Science Core. Though this Center, CMO member Castillo collaborated with Campen to define the in vivo tissue distribution of injested polystyrene or mixed polymer microspheres in mice; they further showed altered metabolism in the colon, liver and brain (Garcia et al., Environ. Health Perspect. 2024). Castillo, Campen and CMO member In worked together to show photoaging of polystyrene microspheres causes oxidative alterations to surface physicochemistry and enhances airway epithelial toxicity (El Hayek et al., Toxicol. Sci. 2023). These and other studies contributed to Castillo’s new funding (NIEHS R01ES032037).

CMO member Xue is defining the mechanisms whereby micronutrients (e.g., iron) and toxic exposures (e.g., microplastics) impact gastrointestinal inflammation and cancer. In a recent study, Xue demonstrated that a colon-specific deletion of the transferrin receptor (TFRC) significantly mitigated the overall incidence of colorectal cancer. He showed that disruption of TFRC leads to a reduction of colonic iron levels and iron-dependent tankyrase activity, which caused stabilization of axis inhibition protein2 (AXIN2) and subsequent repression of the 𝜷-catenin/c-Myc/E2F Transcription Factor1/DNA polymerase delta1 (POLD1) axis (Kim et al., Adv. Sci. 2023). Xue is also working to understand the molecular mechanism of myeloid cells in iron and immune homeostasis. In a recent study, he demonstrated that myeloid Ferritin heavy chain (FTH1) is required for colitis and colitis-associated colorectal cancer (CRC) via maintaining of STAT3 signaling activation under excess iron condition (Liu et al., Inflamm. Bowel Dis. 2023).

Aim 2:  Genome Regulation: To define the mechanisms and pathways by which genome stability, epigenetic alterations, and transcriptional regulation are disrupted in cancer cells.  Significant progress was made by CMO members related to this aim. CMO member Ness is deciphering the molecular events that lead to Adenoid Cystic Carcinoma (ACC), the second most common type of salivary gland tumor that can also arise in other tissues such as lacrimal gland, breast, and skin. Using primary salivary gland ACC patient samples, his work has led to numerous important results that have reshaped our understanding of ACC tumors.  In a recent collaboration with CMO members Kang and Lee and with two other NCI Cancer Centers (MD Anderson, Houston TX and Sylvester Cancer Center, Miami, FL), the team reported a novel molecular biomarker for identifying patients with the worst prognosis (Brayer et al., Cancers 2023). This work also supported the competitive renewal of Ness’s R01 (NIDCR R01DE023222).

CMO member Mao is defining the mechanisms by which DNA damage (e.g., UV photolesions) and DNA repair impact mutation distribution in the cancer genome.  In a recent study, Mao mapped the UV exposure-induced formation of rare 6-4 photoproducts (6-4PP) and atypical thymidine-adenine (TA) photoproducts in DNA.  The work showed that chromatin-bound proteins significantly alter the formation of these photoproducts in a manner distinct from the more common UV-induced cyclobutane pyrimidine dimer (CPD) lesions.  Further, the study showed that 6-4PP hotspots promote UV mutagenesis (Bohm et al., Proc. Natl. Acad. Sci. 2023).  Mao is also working to understand the molecular mechanism of transcription-coupled nucleotide excision repair (TC-NER), a unique repair pathway dealing with transcription blockage (Hoag et al. Environ, Mol. Mutagen. 2024). A new NCI grant is investigating the hypothesis that the TC-NER initiation factor, Cockayne syndrome B (CSB) protein, binds to DNA damage-arrested RNA Polymerase II (Pol II) and evicts the elongation factor Spt4-Spt5 from Pol II, thereby switching Pol II from transcription to DNA repair (NCI R01CA273458).

Tomkinson continues his studies focused on the mechanisms and regulation of DNA replication and repair in non-malignant and cancer cells with the translational goal of developing DNA ligase inhibitors to exploit abnormalities in DNA replication and repair in cancer cells. On-going studies with Dr. van Houten (University of Pittsburgh) examining the different effects of inhibiting mitochondrial DNA ligase III on mitochondrial function in cancer and non-malignant cells formed the basis of a successful grant renewal (NIEHS R01 ES012512-17, Tomkinson PI) with CMO member collaborators, Mandell and Sallmyr. Previously, in collaboration with Dr. Madhusudan (University of Nottingham), Tomkinson identified DNA ligase I as a prognostic indicator and a potential therapeutic target in ovarian cancer. Given the well-established role of DNA ligase I in DNA replication, Tomkinson has examined the effects of genetic and chemical induced DNA ligase I deficiency. These studies revealed that there are remarkably few changes in protein association with newly synthesized DNA in the absence of DNA ligase I (Bhandari et al., Sci. Rep. 2023) and that chemical inhibition of DNA ligase I has different effects on the replication fork compared with genetic inactivation. A new NCI grant (NCI R01 CA276837) with co-I Leslie (CT) and CMO members Steinkamp and Sallmyr is evaluating the activity of DNA ligase I inhibitors in ovarian cancer. Tomkinson is a co-investigator on a recently funded DoD grant (W81XWH2210754, Leslie PI) led by Leslie (CT) to determine the effects of p53 reactivation in advanced endometrial cancer. Tomkinson is also a co-investigator on a grant (NCI U01 CA232505; Belinsky PI) to determine whether the capacity to repair DNA damaged induced by airborne toxicants is a predictor for lung cancer.

CMO members Fan and Lake collaborated with Tomkinson to report novel insights into how the Cockayne syndrome protein B (CSB), an ATP-dependent chromatin remodeler, collaborates with Poly(ADP-ribose) polymerase I (PARP1) in the repair of oxidative DNA lesions.  They showed that PARP1 and PARP2 promote recruitment of CSB to oxidatively-damaged DNA. CSB, in turn, contributes to the recruitment of XRCC1, and histone PARylation factor 1 (HPF1), and promotes histone PARylation, to regulate single-strand break repair (SSBR) mediated by PARP1 and PARP2. Their work indicates that CSB-mediated SSBR occurs primarily at actively transcribed DNA regions, raising the possibility that SSBR is executed by different mechanisms based on the transcription status (Bilkis et al., Nucleic Acids Res. 2023).  The team of Fan and Lake are currently leveraging two grants to test the significance of transcription-associated single-strand break repair (TA-SSBR) in ovarian cancer cells and assessing the potential of targeting this process for cancer therapy (NCI P50CA265793 subproject; NCI R21CA286210).

Belinsky’s research employs interdisciplinary programs of translational science largely focused on epigenetics and lung cancer and alternative nicotine-containing products and health effects.  Working with CMO member, Tellez, they showed that flavored e-cigarette product aerosols induced transformation of human bronchial epithelial cells mediated through reprogramming of the transcriptome and methylome (Tellez et al., Lung Cancer 2023).

Aim 3:  Cellular Signaling and the Tumor Microenvironment: To determine how cell signaling pathways, cellular activities and cell-cell interactions are altered during cancer initiation and progression and within the tumor microenvironment.  CMO members Steinkamp, Hudson, Ness, and Wandinger-Ness, in collaboration with Pankratz (CCPS) and Adams (CT), demonstrated that humanized mice engrafted with human CD34+ cord blood-derived hematopoietic stem cells and bearing patient-derived xenografts (PDXs) establish an immune tumor microenvironment like that reported for patients with ovarian cancer (Steinkamp et al., Cancer Res. Comm. 2023).  This humanized model supports PDX growth that retains the genetic heterogeneity of the primary tumor and exemplifies the original tumor morphology with the added advantage of creating an immune tumor microenvironment with human myeloid and T cell infiltration.  These models will facilitate more clinically relevant investigations of immune cell recruitment, cancer cell/immune cell interactions, and novel therapeutics. Indeed, Adams (CT) included this model in a project entitled "Pilot study of the interaction of estrogen with DNA repair capacity in ovarian tumorigenesis", which is funded from The Ovarian Cancer Alliance of Greater Cincinnati. This model is also being utilized by Serda (CT) member in a collaborative NCI grant (at 10%ile) with Steinkamp.

1. Lidkeuses high-resolution microscopy and single molecule tracking with biophysical and functional read-outs to interrogate the molecular mechanisms of signaling by receptor tyrosine kinases and immunoreceptors (D. Lidke et al., Cancers (Basel) 2023). A newly renewed MIRA grant (NIGMS 2R35 GM126934) funds the D. Lidke laboratory’s investigations of the dynamics of early signaling events that cannot be obtained using traditional biochemical (population-based) techniques.  The central goal is to develop a unique toolbox that includes state-of-the-art microscopy methods, biophysical and functional read-outs, in an integrated approach to provide a comprehensive picture of how protein-protein dynamics regulate tyrosine kinase signaling downstream of immunoreceptors and growth factor receptors.  In an ongoing MPI grant with Dr. Lemon (Yale Cancer Biology Inst.), D. Lidke and CMO member K. Lidke used single-particle tracking (SPT) and Förster resonance energy transfer imaging to examine how each domain of EGFR contributes to receptor oligomerization and the rate of receptor diffusion in the cell membrane. Although the extracellular region of EGFR is sufficient to drive receptor dimerization, they found that the EGF-induced EGFR slowdown seen by SPT requires higher-order oligomerization-mediated in part by the intracellular tyrosine kinase domain when it adopts an active conformation. These findings are important as they provide important insight into the interactions required for higher-order EGFR assemblies involved in EGF signaling (Mudumbi et al., Cell Rep. 2024).

Ozbun extended work demonstrating the antiviral effects of FDA-approved MEK inhibitors in oncogenic human papillomavirus (HPV)-infected three-dimensional tissue models to a murine preclinical model of HPV tumorigenesis. Collaborating with CMO member Kang, the team showed significant antiviral effects that promote tumor regression in the mouse model (Luna et al., Antiviral Res. 2023), and they received a new grant collaborating with McConville (CT) and Dr. Spurgeon (University of Wisc., Carbone CCC) to formulate and test topical MEK inhibitors in two mouse models of HPV precancers (NIAID R21 AI176571).  Preliminary data on this project look promising and the next step will be seeking an FDA investigational new drug approval for IITs aimed to treat patients with HPV-induced precancers.

Recent recruit, Palanisamy, studies RNA-binding proteins (RPBs) and their contribution to gene expression patterns in oral cancer models.  Specifically, this work has provided significant advances in understanding the molecular function of RBPs HuR and FXR1 and their role in oral epithelial homeostasis and cancer progression. A recent study found that transgenic HuR knockout (KO) failed to form oral tumors in a carcinogen induced cancer model. HuR-KO tumors showed fewer CD4+CD25+FoxP3+ regulatory T cells, more CD8+ T cells, and a smaller tumor volume, suggesting HuR may dampen the immune response during oral cancer progression.  HuR KO animals had fewer Tregs and higher IFN levels than WT tumor-bearing mice, suggesting anticancer action. Finally, the HuR inhibitor pyrvinium pamoate reduced tumor burden by increasing CD8+ infiltration over CD4+, suggesting anticancer effects and offering a novel HNSCC treatment (Majumder et al., Oral Oncol Rep. 2024). Palanisamy also found that the protein methyltransferase PRMT5 plays a role in the processing of arginine methylation of RNA-binding protein, FXR1, which in turn increases its RNA-binding ability. The process of R-methylation enhances the stability of the FXR1 and facilitates the expression of genes in oral cancer cells (Vijayakumar et al., Nucleic Acids Res. 2024).  These findings led to a new understanding of how a network of RBPs mediates post-transcriptional gene activity that participates in biological functions and targets mRNA, miRNA, long non-coding RNA, and proteins.

Marchetti has been further investigating the lab’s recent discovery of a circulating tumor cells (CTC) ribosomal proteins of large/small subunits (RPL/RPS) gene signature directly related to the onset of melanoma brain metastasis (MBM). The discovery of the CTC RPL/RPS gene signature of MBM is relevant because variability in ribosomal composition results in the generation of a “onco-ribosome” which drives increased translation, cell proliferation, and tumorigenesis by means of modulating oncogenic signaling pathways. This suggests that the cell translational machine can have another layer of regulation of gene expression refining CTC-associated prognostication. Ribosome biogenesis is a highly coordinated process between RPL/RPS proteins and rRNA assembly factors. This implies a specific vulnerability of CTCs and suggests the targeting of ribosomal biogenesis significantly affects CTC metastatic states.  These findings provide the conduit for translation to the clinic and set the stage for the development of therapeutic agents to improve melanoma patient care, notably MBM.  Following on this idea, in collaboration with Tawfik (CT), they identified specific ribosomal proteins that drive MBM and extracranial metastasis via CTCs. Dual targeting of cellular translation and proliferation prevented metastasis of aggressive CTC subsets with high RPL/RPS expression. Importantly, they reported a novel real-time metabolic flux analysis of patient-derived melanoma CTCs and altered carbohydrate metabolism during impaired translation in a melanoma-CTC-derived clone (Bowley et al., Cancers (Basel) 2023).