Researchers at the National Institute for Physiological Sciences report an unexpected role for smooth septate junction (sSJ) proteins in controlling growth-related signaling during intestinal differentiation. sSJ proteins, previously characterized as adhesion components, are shown to regulate the spatial dynamics of aPKC, a kinase that promotes proliferation.

The team focused on intestinal progenitor cells, which arise from stem cells and mature into functional epithelial cells. By following normal differentiation, they found that sSJ proteins accumulate at the apical region of progenitors. At the same time, the proliferation-driving enzyme aPKC is progressively removed from this same apical zone, establishing a “junction-linked” zoning pattern.

This positioning is lost when sSJ proteins are absent. In progenitor cells lacking sSJ, aPKC remains persistently localized at the apical cortex. The researchers then asked whether this mislocalization is causal for stem cell behavior rather than merely correlated with differentiation.

Using targeted manipulation to maintain apical aPKC, they were able to trigger excessive intestinal stem cell proliferation. The experiment demonstrates that not only signaling activity, but also its subcellular location within progenitor cells, is essential for keeping stem cell homeostasis intact.

Mechanistically, persistent apical aPKC was found to suppress Kibra, an activator of the Hippo signaling pathway. Normally, Hippo signaling acts to restrict growth and prevent overexpansion. When aPKC occupies the apical cortex, Kibra function is dampened, effectively disabling the proliferation restraint.

The study therefore links cell-cell junction architecture to growth control: sSJ-dependent clearance of aPKC preserves Kibra activity, maintains Hippo-mediated limits, and prevents stem cells from entering an unchecked division program. In effect, differentiated progenitors send a molecular “don’t grow” cue derived from junction proteins.

“Our findings show that differentiating progenitor cells actively regulate stem cell proliferation through cell-cell junction proteins,” said Associate Professor Yasushi Izumi. “This reveals an unexpected signaling role for adhesion molecules beyond connecting neighboring cells.”

While the work was performed in fruit flies, the underlying logic—how adhesion-dependent polarity shapes Hippo/Kibra-driven growth control—may inform broader understanding of epithelial maintenance and cancer development in higher organisms.

Subject of Research: Cells
Article Title: aPKC exclusion from the apical cortex in enteroblasts maintains stem cell homeostasis in Drosophila.
Web References: http://dx.doi.org/10.1083/jcb.202509240
References: 10.1083/jcb.202509240
Image Credits: Yasushi Izumi
Keywords: Cell junctions; Progenitor cells; Stem cells; Drosophila

Central among these discoveries is the revelation that intestinal metabolism critically governs the regeneration and differentiation of intestinal stem cells, a process vital for maintaining gut integrity. The intestinal lining is one of the most rapidly renewing tissues in mammals, with stem cells continuously differentiating to replenish diverse cell types needed for nutrient absorption and microbial defense. MSK researchers used sophisticated genetically engineered mouse models and three-dimensional organoid cultures to dissect how specific metabolites influence the fate decisions of these stem cells within living organisms. Their work highlights alpha-ketoglutarate, a key metabolite traditionally recognized for its role in cellular energy cycles, as a pivotal signaling molecule orchestrating stem cell differentiation toward protective intestinal cell lineages.

This nuanced function of alpha-ketoglutarate reshapes our understanding of metabolic regulation in tissue regeneration. Beyond merely fueling bioenergetic demands, such metabolites appear to act as molecular directors, actively shaping cell identity and tissue architecture during regeneration. In mouse models mimicking ulcerative colitis, a chronic inflammatory disease that compromises intestinal barrier function, supplementation with alpha-ketoglutarate restored deficient differentiation pathways and accelerated mucosal healing. This finding carries substantial weight, as chronic inflammation is a recognized precursor to colorectal cancer. Thus, modulating metabolic pathways to enhance stem cell-driven tissue repair not only offers therapeutic avenues for inflammatory bowel diseases but also for cancer prevention.

Previous investigations by the same lab have implicated alpha-ketoglutarate in enhancing the tumor-suppressive function of p53, the “guardian of the genome.” Given that p53 dysfunction is common in pancreatic and other cancers, boosting alpha-ketoglutarate levels may offer a metabolic approach to reinstate tumor suppression. Taken together, these insights reveal a dual role for metabolites in both maintaining tissue homeostasis and restraining oncogenesis, forging new paths in regenerative medicine and metabolic oncology.

Shifting focus to breast cancer, MSK scientists have uncovered a molecular mechanism driving resistance to hormonal and targeted therapies, mediated by the APOBEC3 family of enzymes. While APOBEC3 proteins are chiefly recognized for their antiviral defenses—inducing mutations to disrupt viral genomes—emerging evidence implicates their mutagenic activity in cancer evolution. Analyzing nearly four thousand patient tumor samples, the research team identified distinct mutational signatures attributable to APOBEC3 enzymes. Crucially, these mutational patterns correlated with shortened progression-free survival among patients undergoing endocrine and targeted treatments, highlighting APOBEC3 activity as a biomarker and contributor to therapeutic failure.

One pivotal mutation linked to APOBEC3-mediated mutagenesis is the loss of RB1, a tumor suppressor gene integral to cell cycle regulation. The accumulation of these mutations fosters genomic instability, enabling cancer cells to evade growth controls and resist therapy. Notably, the presence of APOBEC3-induced changes in pre-treatment tumors underscores their role not only in resistance development but also in the initiation and progression of malignancy. These findings elevate APOBEC3 enzymes as promising targets for therapeutic intervention, potentially disrupting the mutational processes that fuel breast cancer resilience.

In a complementary study probing resistance mechanisms in estrogen receptor-positive (ER+) breast cancer, researchers employed CRISPR-Cas9 genetic screening to spotlight NR2F2, a transcription factor implicated in suppressing estrogen receptor signaling. Endocrine therapies, fundamental to managing ER+ breast cancer, function by blocking estrogen-driven proliferation. However, resistance frequently arises, undermining treatment efficacy. The discovery that NR2F2 modulates gene networks to dampen ER signaling clarifies one pathway through which tumors circumvent hormonal intervention.

Functional assays using patient-derived tumor models demonstrated that pharmacological inhibition or genetic ablation of NR2F2 restored sensitivity to endocrine therapies. This breakthrough paves the way for novel therapeutic combinations that could resensitize resistant tumors by targeting NR2F2-mediated transcriptional repression. Such precision medicine strategies promise to extend the durability of current hormonal treatments and improve patient survival.

Beyond molecular and cellular investigations, MSK’s clinical research has explored integrative therapies to alleviate treatment-related side effects in cancer survivors. A randomized pilot trial evaluated acupuncture’s efficacy in mitigating nocturia—a distressing condition characterized by frequent nighttime urination, which is highly prevalent among men treated for prostate cancer. This condition disrupts sleep and erodes quality of life, often persisting years after cancer treatment completion. The trial enrolled 60 men with a history of varied prostate cancer therapies, including surgery, radiation modalities, and hormone therapy.

Participants randomized to a regimen of weekly acupuncture sessions for ten weeks exhibited a significant reduction in nocturnal urination frequency compared to controls receiving standard care. On average, acupuncture recipients woke up approximately one less time per night, with benefits sustained beyond the intervention period. Importantly, no serious adverse events were associated with the acupuncture treatments. This pilot study offers encouraging evidence supporting acupuncture as a safe, non-pharmacological option to improve urinary symptoms and sleep quality in prostate cancer survivors, meriting further investigation in larger, controlled trials.

Taken together, these multifaceted research advances from MSK embody a holistic approach to cancer science, integrating molecular biology, genetic engineering, metabolic biochemistry, and patient-centered clinical research. They unravel fundamental disease mechanisms while simultaneously advancing tangible therapeutic solutions—from metabolite-based tissue regeneration strategies and targeted inhibition of resistance drivers to integrative therapies enhancing survivorship. As these insights translate into clinical innovations, they hold promise to redefine standards of care across oncology disciplines.

Future research will undoubtedly delve deeper into the mechanistic intricacies unveiled by these studies, elucidating how metabolic cues intersect with genetic pathways to govern cancer initiation, progression, and response to treatment. Furthermore, translating findings regarding APOBEC3 and NR2F2 into targeted drug development could transform therapeutic landscapes, offering new hope for overcoming resistance in aggressive breast cancers. Meanwhile, integrating complementary modalities such as acupuncture into survivorship care exemplifies a patient-centered paradigm addressing the broad spectrum of symptoms experienced by cancer patients beyond tumor control.

Memorial Sloan Kettering’s continued commitment to pioneering interdisciplinary cancer research positions the field toward a future where precision-targeted metabolic modulation, genomic stability preservation, and holistic symptom management converge to optimize outcomes for millions affected by cancer worldwide.

Subject of Research: Cancer Biology and Therapeutics, Metabolic Regulation, Breast and Prostate Cancer Resistance, Integrative Oncology

Article Title: Metabolic Insight Reveals New Frontiers in Cancer Regeneration and Resistance

News Publication Date: 2024

Web References:

• https://www.nature.com/articles/s41586-025-09097-6
• https://www.nature.com/articles/s41588-025-02187-1
• https://www.science.org/doi/10.1126/scitranslmed.adk7786
• https://jamanetwork.com/journals/jamaoncology/article-abstract/2834640

References:

• Chaves-Perez, A., Millman, S., & Lowe, S.W. et al. (2024).
• Chandarlapaty, S. et al. (2024).

Image Credits: Memorial Sloan Kettering Cancer Center

Keywords: Cancer research, Basic research, Prostate cancer, Breast cancer