Biology subjects

Bakhoum, S. F.

Publications and source records attributed to Bakhoum, S. F..

7 recordsLinked to original sources

bioRxiv2026

KIF18A Inhibition as a Therapeutic Strategy in Cancers with Rb Pathway Inactivation

KIF18A inhibition has emerged as a therapeutic strategy for chromosomally unstable cancers, but clinical development is limited by the absence of a deployable predictive biomarker. Here we identify strong, diffuse p16INK4a expression, a well-established surrogate marker of Rb-pathway inactivation, as a predictive biomarker of response to KIF18A inhibition, and show that Rb-pathway inactivation marks a biologically distinct subset of cancers sensitive to this therapeutic approach. In sensitive models, low Rb activity is associated with robust spindle assembly checkpoint signaling and prolonged mitotic arrest following KIF18A inhibition. Weakening the spindle assembly checkpoint in this context is sufficient to confer resistance. Across three independent pan-cancer sensitivity datasets generated with distinct KIF18A inhibitors, Rb-pathway altered models were significantly more sensitive than histology-matched Rb-intact comparators, with the strongest association observed in cancers harboring direct RB1 loss or inactivating mutation. Guided by this mechanism, we retrospectively analyzed p16INK4a expression by immunohistochemistry (IHC) in pre-treatment tumor biopsies from 79 heavily pre-treated high-grade serous ovarian cancer patients across three dose-escalation or expansion cohorts and treated with two different KIF18A inhibitors (sovilnesib and VLS-1488) sharing a common mechanism of action. p16INK4a-high tumors showed substantially higher objective response rates than their p16INK4a-low counterparts (36.0% versus 2.2%; P = 0.0002) and markedly longer progression-free survival (median 24.3 versus 7.9 weeks; hazard ratio, 0.16; P < 0.0001). These findings establish p16INK4a as a mechanistically-based, clinically implementable biomarker of clinical response to KIF18A inhibition that is poised to support pan-cancer development of KIF18A inhibitors guided by Rb-pathway inactivation.

cancer biology↗

bioRxiv2022

Mitotic clustering of pulverized chromosomes from micronuclei

Complex genome rearrangements can be generated by the catastrophic shattering of mis-segregated chromosomes trapped within micronuclei through a process known as chromothripsis. Since each chromosome harbors a single centromere, how acentric fragments derived from shattered chromosomes are inherited between daughter cells during mitosis remains unknown. Here we tracked micronucleated chromosomes by live-cell imaging and show that acentric fragments cluster in close spatial proximity throughout mitosis for biased partitioning to a single daughter cell. Mechanistically, the CIP2A-TOPB1 complex prematurely associates with DNA lesions within ruptured micronuclei during interphase, which poises chromosome fragments for clustering upon mitotic entry. Inactivation of CIP2A or TOPBP1 caused pulverized chromosomes to untether and disperse throughout the mitotic cell, consequently resulting in the mis-accumulation of DNA fragments in the cytoplasm. The inheritance of shattered chromosomes by a single daughter cell suggests that micronucleation can drive complex rearrangements that lack the DNA copy number oscillations characteristic of canonical chromothripsis. Comprehensive analysis of pan-cancer whole-genome sequencing data revealed clusters of DNA copy number-neutral rearrangements - termed balanced chromothripsis - across diverse cancer types resulting in the acquisition of known driver events. Thus, distinct patterns of chromothripsis can be explained by the spatial mitotic clustering of pulverized chromosomes from micronuclei.

cell biology↗

bioRxiv2022

The CD58:CD2 axis is co-regulated with PD-L1 via CMTM6 and governs anti-tumor immunity

The cell autonomous balance of immune-inhibitory and -stimulatory signals is a critical yet poorly understood process in cancer immune evasion. Using patient-derived co-culture models and humanized mouse models, we show that an intact CD58:CD2 interaction is necessary for anti-tumor immunity. Defects in this axis lead to multi-faceted immune evasion through impaired CD2-dependent T cell polyfunctionality, T cell exclusion, impaired intra-tumoral proliferation, and concurrent protein stabilization of PD-L1. We performed genome-scale CRISPR-Cas9 and CD58 coimmunoprecipitation mass spectrometry screens identifying CMTM6 as a key stabilizer of CD58, and show that CMTM6 is required for concurrent upregulation of PD-L1 in CD58 loss. Single-cell RNA-seq analysis of patient melanoma samples demonstrates that most TILs lack expression of primary costimulatory signals required for response to PD-1 blockade (e.g. CD28), but maintain strong CD2 expression, thus providing an opportunity to mobilize a so far therapeutically untapped pool of TILs for anti-tumor immunity. We identify two potential therapeutic avenues, including rescued activation of human CD2-expressing TILs using recombinant CD58 protein, and targeted disruption of PD-L1/CMTM6 interactions. Our work identifies an underappreciated yet critical axis at the nexus of cancer immunity and evasion, uncovers a fundamental mechanism of co-inhibitory and -stimulatory signal balancing, and provides new approaches to improving cancer immunotherapies.

cancer biology↗

bioRxiv2022

Epigenetic dysregulation from chromosomal transit in micronuclei

Chromosomal instability (CIN) and epigenetic alterations are characteristics of advanced and metastatic cancers [1-4], yet whether they are mechanistically linked is unknown. Here we show that missegregation of mitotic chromosomes, their sequestration in micronuclei [5, 6], and subsequent micronuclear envelope rupture [7] profoundly disrupt normal histone post-translational modifications (PTMs), a phenomenon conserved across humans and mice as well as cancer and non-transformed cells. Some of the changes to histone PTMs occur due to micronuclear envelope rupture whereas others are inherited from mitotic abnormalities prior to micronucleus formation. Using orthogonal techniques, we show that micronuclei exhibit extensive differences in chromatin accessibility with a strong positional bias between promoters and distal or intergenic regions. Finally, we show that inducing CIN engenders widespread epigenetic dysregulation and that chromosomes which transit in micronuclei experience durable abnormalities in their accessibility long after they have been reincorporated into the primary nucleus. Thus, in addition to genomic copy number alterations, CIN can serve as a vehicle for epigenetic reprogramming and heterogeneity in cancer.

cancer biology↗

bioRxiv2021

Innate immune signaling drives late cardiac toxicity following DNA damaging cancer therapies

Late cardiac toxicity is a potentially lethal complication of cancer therapy, yet the pathogenic mechanism remains largely unknown, and few treatment options exist. Here we report DNA damaging agents such as radiation and anthracycline chemotherapies induce delayed cardiac inflammation following therapy due to activation of cGAS and STING-dependent type I interferon signaling. Genetic ablation of cGAS-STING-signaling in mice inhibits DNA damage induced cardiac inflammation, rescues late cardiac functional decline, and prevents death from cardiac events. Treatment with a STING antagonist suppresses cardiac interferon signaling following DNA damaging therapies and effectively mitigates cardiotoxicity. These results identify a therapeutically targetable, pathogenic mechanism for one of the most vexing treatment-related toxicities in cancer survivors.

immunology↗

bioRxiv2020

The clinical and molecular significance associated with STING signaling in estrogen receptor-positive early breast cancer

STING signaling in cancer is a crucial component of response to immunotherapy and other anti-cancer treatments. Conversely, STING signaling can promote tumor invasion and metastasis. Currently, there is no robust method of measuring STING activation in cancer. Here, we describe an immunohistochemistry-based assay with digital pathology assessment of STING in tumor cells. Using this novel approach, we identify perinuclear-localized expression of STING (pnSTING) in estrogen receptor-positive (ER+) breast cancer as an independent predictor of good prognosis, associated with immune cell infiltration and upregulation of immune checkpoints. Tumors with low pnSTING are immunosuppressed with increased infiltration of "M2" -polarised macrophages. In ER-disease, pnSTING does not have a significant prognostic role, and STING appears to be uncoupled from interferon responses. Importantly, a gene signature defining low pnSTING expression in ER+ disease is predictive of poor prognosis in independent datasets. Low pnSTING is associated with chromosomal instability, MYC amplification and mTOR signaling, suggesting novel therapeutic approaches for this subgroup.

cancer biology↗

bioRxiv2020

Limited Environmental Serine Confers Sensitivity to PHGDH Inhibition in Brain Metastasis

A hallmark of metastasis is the adaptation of tumor cells to new environments. Although it is well established that the metabolic milieu of the brain is severely deprived of nutrients, particularly the amino acids serine and its catabolite glycine, how brain metastases rewire their metabolism to survive in the nutrient-limited environment of the brain is poorly understood. Here we demonstrate that cell-intrinsic de novo serine synthesis is a major determinant of brain metastasis. Whole proteome comparison of triple-negative breast cancer (TNBC) cells that differ in their capacity to colonize the brain reveals that 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of glucose-derived serine synthesis, is the most significantly upregulated protein in cells that efficiently metastasize to the brain. Genetic silencing or pharmacological inhibition of PHGDH attenuated brain metastasis and improved overall survival in mice, whereas expression of catalytically active PHGDH in a non-brain trophic cell line promoted brain metastasis. Collectively, these findings indicate that nutrient availability determines serine synthesis pathway dependence in brain metastasis, and suggest that PHGDH inhibitors may be useful in the treatment of patients with cancers that have spread to the brain. Statement of SignificanceOur study highlights how limited serine and glycine availability within the brain microenvironment potentiates tumor cell sensitivity to serine synthesis inhibition. This finding underscores the importance of studying cancer metabolism in physiologically-relevant contexts, and provides a rationale for using PHGDH inhibitors to treat brain metastasis.

cancer biology↗