Sankar Jagadeeshan

Dietary phytochemicals play a crucial role in targeting cancer stem cells (CSCs), which are key contributors to tumor recurrence, metastasis, and resistance to conventional therapies. Bioactive compounds from dietary plants have demonstrated significant efficacy in inhibiting critical stem cell pathways, including Wnt/β-catenin, Notch, Hedgehog (Hh), and PI3K/AKT/mTOR signaling, by targeting specific CSC markers. These natural agents effectively disrupt self-renewal mechanisms, reverse the epithelial-mesenchymal transition, and induce apoptosis in various cancer types, thereby mitigating drug resistance. The integration of cancer stem cell-targeting dietary phytochemicals with standard therapies holds promise for synergistic effects, functioning as chemosensitizers and radiosensitizers, and offering a less toxic alternative for cancer treatment. Notably, advancements in the nanoformulation of phytochemicals have overcome bioavailability limitations, enhancing the precision of drug delivery to CSCs. By synthesizing recent research insights, this chapter underscores the role of dietary phytochemicals as a crucial element of precision cancer therapy, contributing to comprehensive strategies aimed at preventing cancer recurrence, overcoming therapy resistance, and inhibiting metastasis by reducing cancer stemness.

Triple-negative breast cancer (TNBC) is an aggressive disease characterized by high metastatic potential and limited treatment options. Protein kinase C-eta (PKCη), an antiapoptotic kinase of the novel PKC subfamily, is associated with poor prognosis in breast cancer patients. Analysis of TNBC tumors revealed that PRKCH (PKCη) expression is linked to an epithelial‒mesenchymal transition (EMT) signature, which is indicative of a metastatic phenotype. Using genetic ablation studies, we showed that PKCη promotes metastasis by enhancing EMT and stemness. Notably, compared with those in PKCη-intact tumors, orthotopic xenografts of PKCη-knockout cells in NSG mice resulted in reduced tumor growth and metastasis. Mechanistically, PKCη functions as a negative regulator of the Hippo pathway by activating YAP. PKCη phosphorylates YAP at Ser128, leading to its stabilization and nuclear translocation, which promotes metastasis. We also demonstrated that PKCη negatively regulates AKT, thereby further sustaining the downregulation of the Hippo pathway. Finally, we show that an evolutionarily conserved peptide encoded by an upstream open reading frame (uORF) preceding the PKCη coding sequence functions as a PKCη degrader, activating the Hippo pathway and promoting YAP degradation. Together, our findings reveal a PKCη-driven signaling axis that regulates the Hippo–YAP pathway in TNBC metastasis, highlighting the potential therapeutic vulnerability of this aggressive disease.

Supplementary Figures S1 to S6 with figure legends

Supplementary Materials and Methods

The survival rate for patients with head and neck cancer (HNC) diagnosed with cervical lymph node (cLN) or distant metastasis is low. Genomic alterations in the HRAS oncogene are associated with advanced tumor stage and metastasis in HNC. Elucidation of the molecular mechanisms by which mutated HRAS (HRASmut) facilitates HNC metastasis could lead to improved treatment options for patients. Here, we examined metastasis driven by mutant HRAS in vitro and in vivo using HRASmut human HNC cell lines, patient-derived xenografts, and a novel HRASmut syngeneic model. Genetic and pharmacological manipulations indicated that HRASmut was sufficient to drive invasion in vitro and metastasis in vivo. Targeted proteomic analysis showed that HRASmut promoted AXL expression via suppressing the Hippo pathway and stabilizing YAP1 activity. Pharmacological blockade of HRAS signaling with the farnesyltransferase inhibitor tipifarnib activated the Hippo pathway and reduced the nuclear export of YAP1, thus suppressing YAP1-mediated AXL expression and metastasis. AXL was required for HRASmut cells to migrate and invade in vitro and to form regional cLN and lung metastases in vivo. In addition, AXL-depleted HRASmut tumors displayed reduced lymphatic and vascular angiogenesis in the primary tumor. Tipifarnib treatment also regulated AXL expression and attenuated VEGFA and VEGFC expression, thus regulating tumor-induced vascular formation and metastasis. Our results indicate that YAP1 and AXL are crucial factors for HRASmut-induced metastasis and that tipifarnib treatment can limit the metastasis of HNC tumors with HRAS mutations by enhancing YAP1 cytoplasmic sequestration and downregulating AXL expression.Significance:Mutant HRAS drives metastasis of head and neck cancer by switching off the Hippo pathway to activate the YAP1–AXL axis and to stimulate lymphovascular angiogenesis.

Supplementary Figures S1 to S6 with figure legends

Supplementary Materials and Methods

Supplementary Figures S1 to S6 with figure legends

Supplementary Materials and Methods