Shun-Fat Lau

Crypt fixation is an early and essential event of colorectal cancer initiation 1–6. It is an evolutionary process where precancerous stem cells compete with their healthy neighbors for monoclonal fixation of intestinal crypts 1–6. This competition involves stochastic interaction between three cell populations, oncogene mutant clones, competing wild-type clones and the cells populating their microenvironment. Interactions between competing WT and mutant clones are well studied; however, the impact of the microenvironment cells on crypt fixation, has been challenging to quantify 1–6. This is due to the absence of suitable experimental and theoretical models to study three-way stochastic interactions between competing clones and cells in their microenvironment. To overcome this challenge, we integrated established mosaic clonal selection models1,7,8 and immune depletion models9 with the theoretical framework provided by Stochastic Conveyor Belt model 10,11. Using this approach, we quantified the selective advantage of colonic stem cells with the BRAFV600E mutation, one of the most prevalent human oncogenes. We showed that BRAFV600E confers a selective advantage to colonic stem cells but approximately half of the clones are destined for clonal extinction. We show mechanistically that clonal extinction of these precancerous cells is actively mediated by adaptive immune system. Specific depletion of regulatory T cells or targeted deletion of Major Histocompatibility Complex Class II (MHCII) or interleukin 10 receptor A (IL10RA) on the BRAFV600E mutated clones, prevented their extinction. Overall, these findings reveal a new immune sensing mechanism whereby Tregs recognize and eliminate precancerous stem cells before malignant transformation. Understanding this interplay between microenvironment and stem cell dynamics at tumor initiation will enable the development of immunoprevention strategies against colon cancer initiation, rather than treat existing tumors. *Birgit Tschiatschek & Miraal Maqsood contributed equally.

Background: Trastuzumab deruxtecan (T-DXd) has transformed the treatment paradigm for HER2-expressing breast cancer, including HER2-low disease. However, biomarkers associated with T-DXd activity remain poorly defined. We conducted a comprehensive analysis of clinical, genomic, and immune correlates of T-DXd outcomes to identify molecular determinants of therapeutic benefit and resistance. Methods: We retrospectively analyzed 2 independent cohorts of patients with advanced breast cancer treated with T-DXd at Dana-Farber Cancer Institute and Yale Cancer Center between 2018 and 2024. We included patients with ≥2 tumor blocks with HER2 immunohistochemistry (IHC) assessments prior to T-DXd. Clinical data on 524 patients were manually reviewed, and genomic profiling and immune microenvironment assessments were performed on a subset of patients. Multivariable Cox proportional hazards models evaluated associations between molecular features and overall survival (OS) and time to next treatment (TTNT). Results: Among 524 patients, HER2 IHC discordance between sequential tumor biopsies was observed in 20% of patients and was independently associated with significantly worse OS (hazard ratio [HR] = 0.67; P = .012) and TTNT (HR = 0.65; P = .002), resembling outcomes seen in HER2 0 tumors. Genomic analysis revealed that PTEN mutations correlated with inferior TTNT (HR = 2.2; q = 0.068), whereas ERBB2 amplifications predicted improved OS and TTNT. An inflamed tumor microenvironment determined by digital pathology was associated with significantly poorer TTNT outcomes (median TTNT = 5.5 months) compared with immune-desert phenotypes (median OS = 9.6 months, P = .03). Conclusions: This study identifies HER2 IHC discordance and specific genomic and immune features as prognostic biomarkers of T-DXd efficacy. These findings warrant prospective validation and may inform biomarker-driven strategies to optimize T-DXd therapy in HER2-expressing malignancies.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observe comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identifies distinct non-small cell lung cancer-like (NSCLC-like, KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling reveals stable mutational but shifting transcriptomic landscapes over time. Here we show, elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression in NSCLC-like LCNECs, and higher levels of DLL3 in SCLC-like LCNECs. Immunofluorescence confirms FGL-1 expression in NSCLC-like LCNECs, and H&E slide analyses indicates fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

Pulmonary large cell neuroendocrine carcinoma (LCNEC) is a rare, aggressive lung tumor marked by significant molecular heterogeneity. In a study of 590 patients across two independent cohorts, we observed comparable overall survival across treatment regimens (chemotherapy, chemoimmunotherapy, immunotherapy) without unexpected adverse events. Genomic analysis identified distinct NSCLC-like (KEAP1, KRAS, STK11 mutations) and SCLC-like (RB1, TP53 mutations) LCNEC subtypes, with 80% aligning with SCLC transcriptional profiles. Serial sampling revealed stable mutational but shifting transcriptomic landscapes over time. NSCLC-like LCNECs showed elevated FGL-1 (a LAG-3 ligand) and SPINK1 expression, while SCLC-like subtypes expressed higher levels of DLL3. Immunofluorescence confirmed FGL-1 in NSCLC-like LCNECs, and H&E slide analyses indicated fewer tumor-infiltrating lymphocytes in LCNECs versus other lung cancers. These findings highlight LCNEC’s distinct immunogenomic profile, supporting future investigations into LAG-3, SPINK1, and DLL3-targeted therapies.

In Alzheimer’s disease (AD), sensome receptor dysfunction impairs microglial danger-associated molecular pattern (DAMP) clearance and exacerbates disease pathology. Although extrinsic signals, including interleukin-33 (IL-33), can restore microglial DAMP clearance, it remains largely unclear how the sensome receptor is regulated and interacts with DAMP during phagocytic clearance. Here, we show that IL-33 induces VCAM1 in microglia, which promotes microglial chemotaxis toward amyloid-beta (Aβ) plaque-associated ApoE, and leads to Aβ clearance. We show that IL-33 stimulates a chemotactic state in microglia, characterized by Aβ-directed migration. Functional screening identified that VCAM1 directs microglial Aβ chemotaxis by sensing Aβ plaque-associated ApoE. Moreover, we found that disrupting VCAM1–ApoE interaction abolishes microglial Aβ chemotaxis, resulting in decreased microglial clearance of Aβ. In patients with AD, higher cerebrospinal fluid levels of soluble VCAM1 were correlated with impaired microglial Aβ chemotaxis. Together, our findings demonstrate that promoting VCAM1–ApoE-dependent microglial functions ameliorates AD pathology.

Microglia maintain brain homeostasis through their ability to survey and phagocytose danger‐associated molecular patterns (DAMPs). In Alzheimer's disease (AD), microglial phagocytic clearance regulates the turnover of neurotoxic DAMPs including amyloid beta (Aβ) and hyperphosphorylated tau. To mediate DAMP clearance, microglia express a repertoire of surface receptors to sense DAMPs; the activation of these receptors subsequently triggers a chemotaxis‐to‐phagocytosis functional transition in microglia. Therefore, the interaction between microglial receptors and DAMPs plays a critical role in controlling microglial DAMP clearance and AD pathogenesis. However, there is no comprehensive overview on how microglial sensome receptors interact with DAMPs and regulate various microglial functions, including chemotaxis and phagocytosis. In this review, we discuss the important axes of receptor–ligand interaction that control different microglial functions and their roles in AD pathogenesis. First, we summarize how the accumulation and structural changes of DAMPs trigger microglial functional impairment, including impaired DAMP clearance and aberrant synaptic pruning, in AD. Then, we discuss the important receptor–ligand axes that restore microglial DAMP clearance in AD and aging. These findings suggest that targeting microglial chemotaxis—the first critical step of the microglial chemotaxis‐to‐phagocytosis state transition—can promote microglial DAMP clearance in AD. Thus, our review highlights the importance of microglial chemotaxis in promoting microglial clearance activity in AD. Further detailed investigations are essential to identify the molecular machinery that controls microglial chemotaxis in AD. image

Significance: Adult hippocampal neurogenesis, the lifelong generation of neurons in the dentate gyrus, is important for brain functioning, including learning, memory, and mood regulation. Its dysregulation is associated with cognitive decline and mood disorders. We discovered that the Rho GTPase-activating protein, α2-chimaerin, is essential for adult hippocampal neurogenesis, as it precisely regulates the transition of neural stem cells (NSCs) into intermediate progenitor cells (IPCs). Conditional knockout of α2-chimaerin in adult NSCs in the mouse hippocampus resulted in a loss of the Klotho-expressing NSC population and the premature differentiation of NSCs into IPCs, which impaired neuron production. These mice also exhibited compromised hippocampal synaptic plasticity and anxiety/depression-like behaviors. Thus, our findings revealed that α2-chimaerin is important in adult hippocampal neurogenesis.