Elevated Transglutaminase-2 in SOX10-Deficient Melanoma Promotes Tumor Onset and Decreases Intratumoral CD4+ T Cells.

Melanoma heterogeneity contributes to therapy resistance and immune evasion. The loss of SOX10, a neural crest lineage-specific transcription factor, leads to phenotypic switching from a proliferative cell state to an invasive, drug-tolerant cell state. SOX10-deficient cells are able to persist during immunotherapy treatment, highlighting the need to characterize the factors that regulate immune evasion downstream of SOX10 loss.

SOX10 Loss Sensitizes Melanoma Cells to Cytokine-Mediated Inflammatory Cell Death.

Unlabelled: The transcription factor, SOX10, plays an important role in the differentiation of neural crest precursors to the melanocytic lineage. Malignant transformation of melanocytes leads to the development of melanoma, and SOX10 promotes melanoma cell proliferation and tumor formation. SOX10 expression in melanomas is heterogeneous, and loss of SOX10 causes a phenotypic switch toward an invasive, mesenchymal-like cell state and therapy resistance; hence, strategies to target SOX10-deficient cells are an active area of investigation.

APC Loss Prevents Doxorubicin-Induced Cell Death by Increasing Drug Efflux and a Chemoresistant Cell Population in Breast Cancer.

Chemoresistance is a major health concern affecting cancer patients. Resistance is multifactorial, with one mechanism being the increased expression of ABC transporters (such as MDR1 and MRP1), which are drug efflux transporters capable of preventing intracellular accumulation of drugs and cell death. Our lab showed that the loss of caused an intrinsic resistance to doxorubicin (DOX), potentially through an enhanced tumor-initiating cell (TIC) population and the increased activation of STAT3 mediating the expression of MDR1 in the absence of WNT being activated.

Combating CHK1 resistance in triple negative breast cancer: EGFR inhibition as potential combinational therapy.

Triple negative breast cancer (TNBC) is marked by a lack of expression of the Estrogen Receptor, Progesterone Receptor, and human epidermal growth factor receptor 2. Therefore, targeted therapies are being investigated based on the expression profiles of tumors. Due to the potential for acquired and intrinsic resistance, there is a need for combination therapy to overcome resistance.

Wnt-Independent and Wnt-Dependent Effects of APC Loss on the Chemotherapeutic Response.

Resistance to chemotherapy occurs through mechanisms within the epithelial tumor cells or through interactions with components of the tumor microenvironment (TME). Chemoresistance and the development of recurrent tumors are two of the leading factors of cancer-related deaths. The Adenomatous Polyposis Coli (APC) tumor suppressor is lost in many different cancers, including colorectal, breast, and prostate cancer, and its loss correlates with a decreased overall survival in cancer patients.

APC loss affects DNA damage repair causing doxorubicin resistance in breast cancer cells.

Chemoresistance is one of the leading causes of cancer-related deaths in the United States. Triple negative breast cancer (TNBC), a subtype lacking the known breast cancer receptors used for targeted therapy, is reliant on chemotherapy as the standard of care. The Adenomatous Polyposis Coli (APC) tumor suppressor is mutated or hypermethylated in 70% of sporadic breast cancers with APC-deficient tumors resembling the TNBC subtype.

Cftr Modulates Wnt/β-Catenin Signaling and Stem Cell Proliferation in Murine Intestine.

Background & Aims: Cystic fibrosis (CF) patients and CF mouse models have increased risk for gastrointestinal tumors. CF mice show augmented intestinal proliferation of unknown etiology and an altered intestinal environment. We examined the role of the cystic fibrosis transmembrane conductance regulator (Cftr) in Wnt/β-catenin signaling, stem cell proliferation, and its functional expression in the active intestinal stem cell (ISC) population.

APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation.

Resistance to chemotherapy is one of the leading causes of death from breast cancer. We recently established that loss of (APC) in the Mouse Mammary Tumor Virus - Polyoma middle T (MMTV-PyMT) transgenic mouse model results in resistance to cisplatin or doxorubicin-induced apoptosis. Herein, we aim to establish the mechanism that is responsible for APC-mediated chemotherapeutic resistance.

Cellular chloride and bicarbonate retention alters intracellular pH regulation in Cftr KO crypt epithelium.

Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR), an anion channel providing a major pathway for Cl(-) and HCO3 (-) efflux across the apical membrane of the epithelium. In the intestine, CF manifests as obstructive syndromes, dysbiosis, inflammation, and an increased risk for gastrointestinal cancer. Cftr knockout (KO) mice recapitulate CF intestinal disease, including intestinal hyperproliferation.