Biology subjects

Diehl, J. A.

Publications and source records attributed to Diehl, J. A..

4 recordsLinked to original sources

bioRxiv2026

Mono-ADP-ribosylation-driven immunosuppression and cross-resistance to therapy through cancer cell intrinsic and extrinsic mechanisms

Mono-ADP-ribosylation (MARylation) is emerging as an important regulator of anti-cancer immunity and immunosuppressive tumor microenvironment (TME). Our previous studies showed that PARP11, one of several enzymes that facilitate MARylation, regulates the activities of intratumoral cytotoxic T lymphocytes (CTLs) and regulatory T cells (Tregs). Here, we demonstrate that stimuli such as adenosine, epinephrine, or glucagon-like peptide-1 (GLP1) induced PARP11 in cancer cells. Upregulation of PARP11 in cancer cells led to PARP11-mediated MARylation, ubiquitination, and accelerated degradation of MHC-I through the autophagy-lysosomal pathway. Induction of PARP11 protected cancer cells from killing by specific CTLs and stimulated tumor growth and progression. Genetic ablation of PARP11 attenuated MHC-I MARylation, ubiquitination, and interaction with autophagy receptors. Pharmacologic inhibition of PARP11 in pancreatic ductal adenocarcinoma (PDAC) cells restored their MHC-I levels, sensitized them to killing by CTLs, inhibited tumor growth, and impeded their initial resistance to chemotherapy and their acquired resistance to targeted therapy with RAS inhibitors. Moreover, inhibition of PARP11 prevented hyperprogressive disease in a mouse melanoma model treated with immune checkpoint inhibitors (ICBs), suggesting that PARP11 is a major therapeutically actionable driver of immunosuppression in tumors. SYNOPSISInduction of PARP11 in the tumor microenvironment mediates immunosuppression. This study reports that PARP11-driven MARylation and ubiquitination of MHC-I in cancer cells drives immune evasion, tumor growth and resistance to therapies.

cancer biology↗

bioRxiv2026

SPTBN2 promotes an immunosuppressive tumor microenvironment and cross-resistance to anti-cancer therapies

Immunosuppressive tumor microenvironment (TME) inactivates CD8+ cytotoxic lymphocytes (CTLs). Here, we identify SPTBN2 spectrin as a key immunosuppressive regulator induced in CTLs in response to nutritional deficit. In human pancreatic and colorectal cancers, SPTBN2 expression negatively correlated with CTL infiltration and patients survival. In TME of mouse pancreatic and colorectal adenocarcinomas, SPTBN2 inactivated intratumoral CTLs, stimulated tumor growth and conferred cross-resistance to anti-cancer therapies. SPTBN2 knockout protected CAR T-cells from trogocytosis and increased their memory state. SPTBN2 maintained levels of cell surface proteins such as BTLA that undermine CAR T-cell cytotoxicity and promote exhaustion. Re-expression of BTLA largely reversed phenotypes in SPTBN2-deficient CAR T-cells. In manufactured CAR T cells, SPTBN2 was associated with their clinical failure in pediatric patients with leukemia. Accordingly, ablation of SPTBN2 in CAR T-cells increased their cytotoxicity, in vivo persistence and therapeutic effects indicating that SPTBN2 can be targeted to increase the efficacy of anti-cancer therapies.

cancer biology↗

bioRxiv2025

PML1-Mediated Feedforward Loop Through PI3K and MAPK Axes Drives Endocrine Resistance

Treatment of estrogen receptor-positive (ER+) breast cancer is significantly hindered by endocrine resistance. We identified PML1 as a key therapeutic entity that can be targeted to overcome resistance. Endocrine-resistant breast cancer cells share three key characteristics: elevated PML1 protein levels, enhanced activity of PI3K, MAPK, or both signaling pathways, and reduced ER activity. We developed a PML1 gene signature that predicts poor prognosis and correlates strongly with PI3K, MAPK, and endocrine resistance gene signatures, as evident by cellular studies, scRNA-seq analysis, and spatial transcriptomics of endocrine therapy-treated tumors. This signature is present in endocrine-resistant breast cancer cells harboring the Y537S ER mutation. We consistently demonstrate high PML1 protein levels across cells resistant to various treatments, including 4-hydroxytamoxifen, fulvestrant, elacestrant, and CDK4/6 inhibitors. Furthermore, treatments with these therapeutic agents or knockdown of ESR1 mRNA also increase PML1 protein levels. Mechanistically, we show that ER inhibition through fulvestrant treatment activates PI3K and MAPK signaling, which enhance PML1 protein stability and synthesis. PML1 then drives a feedforward loop by stimulating the expression of cytokine and growth factor mRNAs, including CCL5 and HBEGF, further amplifying PI3K and MAPK signaling. Consequently, in endocrine-resistant cells, endocrine therapies, while inactivating ER, paradoxically reinforce this loop through increased PI3K/MAPK activation and PML1 protein accumulation, ultimately compromising therapeutic efficacy. Finally, we demonstrated that arsenic trioxide, an FDA-approved, PML-reducing drug, effectively disrupts this feedforward loop, offering a promising strategy for treating resistant metastatic breast cancer. STATEMENT OF SIGNIFICANCEEndocrine resistance remains a major obstacle in treating estrogen receptor-positive metastatic breast cancer. Our study identifies PML1 as a central mediator of this resistance, revealing how it maintains a self-reinforcing signaling network through PI3K and MAPK pathways by enhancing the production of cytokines and growth factors. The clinical significance of our findings is threefold: we establish PML1 as a biomarker for therapy resistance, demonstrate its mechanistic role in treatment failure, and show that FDA-approved arsenic trioxide can disrupt PML1-driven resistance. These insights provide a direct path to clinical translation, as combining arsenic trioxide with existing therapies could benefit patients with limited treatment options.

cancer biology↗

bioRxiv2023

ALDH2 dysfunction accelerates ESCC pathogenesis

The alcohol metabolite acetaldehyde is a potent human carcinogen. Aldehyde dehydrogenase 2 (ALDH2) is the primary enzyme that detoxifies acetaldehyde in the mitochondria. Acetaldehyde accumulates and causes genotoxic stress in cells expressing the dysfunctional ALDH2E487K mutant protein linked to ALDH2*2, the single nucleotide polymorphism highly prevalent amongst East Asians. Chronic alcohol users with heterozygous ALDH2*2 display an increased risk for the development of esophageal squamous cell carcinoma (ESCC) and other alcohol-related cancers. However, how ALDH2 influences ESCC pathobiology is incompletely understood. Herein, we characterize how ESCC and preneoplastic cells respond to alcohol exposure using cell lines, three dimensional organoids, and xenograft models. We find that alcohol exposure results in increased organoid formation and tumor growth concurrent with increased reactive oxygen species (ROS), increased DNA damage, and the enrichment of putative cancer stem cells (CSCs) characterized by high CD44 expression. Pharmacological activation of ALDH2 function by Alda-1 inhibits this phenotype, indicating that acetaldehyde is the primary driver of these changes. ALDH2 dysfunction also affects response to a commonly used chemotherapy for the treatment of ESCC. We find that Aldh2 dysfunction facilitated enrichment of CSCs following cisplatin-induced cell death and oxidative stress in murine organoids. Together, these data provide evidence that alcohol exposure, results in more aggressive tumors through enrichment of CSCs, which is augmented by ALDH2 dysfunction.

cancer biology↗