Biology subjects

Robertson, M. R.

Publications and source records attributed to Robertson, M. R..

3 recordsLinked to original sources

bioRxiv2025

Opposing effects of systemic and pancreas-specific inhibition of BCKDK on pancreatic carcinogenesis

Branched-chain amino acid (BCAA) metabolism is perturbed in patients with pancreatic cancer, but the contribution of systemic or pancreas-intrinsic BCAA catabolism to pancreatic carcinogenesis is unclear. We show here that pancreas-specific loss of DBT, the E2 subunit of the branched-chain keto-acid dehydrogenase (BCKDH) complex required for BCAA oxidation, strikingly exacerbates premalignant pancreatic intraepithelial neoplasia (PanIN) lesions in KC (p48-Cre;KrasLSL-G12D/+) mice. However, deletion of upstream enzyme BCAT2 neither phenocopied nor rescued loss of DBT in KC mice, ruling out involvement of both upstream and downstream metabolites as mediators of PanIN promotion. Instead, we observed that DBT deficiency led to loss of the kinase BCKDK, a negative regulator of the BCKDH complex, and that, remarkably, pancreas-specific loss of BCKDK phenocopied DBT deficiency in accelerating PanIN formation. These data thus support a model in which pancreas BCKDK restrains tumorigenesis. In contrast, systemic treatment of KC mice with the BCKDK inhibitor BT2, which inhibits BCKDH phosphorylation across many tissues except the pancreas, reduced PanIN formation and preserved normal acinar area. Together the data reveal the promotion of BCAA catabolism systemically, but not within the pancreas, as a promising intervention strategy to suppress tumor initiation.

cancer biology↗

bioRxiv2025

The H3K36M oncohistone inhibits NSD2 to activate a SETD2-dependent antiviral-like immune response in KRAS-driven lung cancer

Mutations in histone 3 at or near lysine 36 (H3K36) have dominantly acting oncogenic effects in multiple tumor types by limiting H3K36-directed methyltransferases. Paradoxically, we find that expression of the H3K36M oncohistone unexpectedly inhibits tumor formation in KRAS-driven lung adenocarcinoma by inducing a potent immune-mediated tumor clearance. Mechanistically, oncohistone expression derepresses endogenous retroviral element transcription, results in the accumulation of double-stranded RNA (dsRNA), and activates an innate antiviral-like immune response that eradicates tumor growth. Surprisingly, while inactivation of the H3K36 di-methyltransferase NSD2 replicated all effects of oncohistone expression, inactivation of the H3K36 tri-methyltransferase SETD2 abolished element derepression and all associated downstream anti-cancer effects that are induced by oncohistone expression. These observations restructure our understanding of the roles of H3K36 methylation, the consequences of its deregulation in cancer, and shape our expectations for therapeutic interventions targeting H3K36 methyltransferases.

cancer biology↗

bioRxiv2025

Tumor suppressor genotype influences the extent and mode of immunosurveillance in lung cancer

The impact of cancer driving mutations in regulating immunosurveillance throughout tumor development remains poorly understood. To better understand the contribution of tumor genotype to immunosurveillance, we generated and validated lentiviral vectors that create an epi-allelic series of increasingly immunogenic neoantigens. This vector system is compatible with autochthonous Cre-regulated cancer models, CRISPR/Cas9-mediated somatic genome editing, and tumor barcoding. Here, we show that in the context of KRAS-driven lung cancer and strong neoantigen expression, tumor suppressor genotype dictates the degree of immune cell recruitment, positive selection of tumors with neoantigen silencing, and tumor outgrowth. By quantifying the impact of 11 commonly inactivated tumor suppressor genes on tumor growth across neoantigenic contexts, we show that the growth promoting effects of tumor suppressor gene inactivation correlate with increasing sensitivity to immunosurveillance. Importantly, specific genotypes dramatically increase or decrease sensitivity to immunosurveillance independently of their growth promoting effects. We propose a model of immunoediting in which tumor suppressor gene inactivation works in tandem with neoantigen expression to shape tumor immunosurveillance and immunoediting such that the same neoantigens uniquely modulate tumor immunoediting depending on the genetic context. One Sentence SummaryHere we uncover an under-appreciated role for tumor suppressor gene inactivation in shaping immunoediting upon neoantigen expression.

cancer biology↗